During FYI 2013-2014, a number of major accomplishments have driven this project closer to meeting its goals of quantifying schizophrenia- and schizophrenia-risk associated cortical dysfunction, identifying candidate genetic contributors to this dysfunction, and assessing the importance of these contributors to treatment-relevant outcomes. For instance, recent work derived from this project has identified important cognitive impairments in perceptual categorical judgments (Weickert, Terrazas et al. 2014) and category-restricted verbal generation (Nicodemus, Elvevag et al. 2014). The latter observation has been particularly fruitful for elaborating putative schizophrenia risk mechanisms. Using neuropsychological testing and specialized computational linguistic metrics, we employed a well-validated category verbal fluency task to assay cortical function in patients with schizophrenia, their siblings, and healthy controls. We were able not only to discover task performance measurements that were both impaired in schizophrenia and altered in individuals with greater schizophrenia risk (siblings), but also to then test whether specific genetic risk factors (SNPs previously associated with schizophrenia) might impact these same measurements. Indeed, this series of experiments generated novel evidence supporting a role for DISC1, ZNF804A and KIAA0319 as important genetic predictors of these cognitive schizophrenia risk phenotypes. (Nicodemus, Elvevag et al. 2014) Additionally, we have advanced our investigations of medication response mechanisms, leading to several new neurocognitive and molecular discoveries. For example, we have helped to identify novel, preliminary evidence for antipsychotic medication effects on aspects of probabilistic association learning (Weickert, Mattay et al. 2013). In a second instance of this line of inquiry, research completed this year has been able to support an important new role for variation in the neurexin 1 (NRXN1) gene, which has previously been associated with autism, intellectual disability, epilepsy, developmental delay, and also schizophrenia. We conducted a double blind, placebo controlled trial in 54 patients with schizophrenia from the NIMH inpatient study to show a significant association of NRXN1 SNPs rs12467557 and rs10490162 with antipsychotic response. Individuals homozygous for the A allele in both SNPs showed statistically significant improvement in positive and negative symptoms, general psychopathology and thought disturbance. However, patients who were carriers of the G allele showed no overall response. (Jenkins, Apud et al. 2014) Ongoing work in this same vein investigates DRD2, which codes for the D2 receptor a target of modern antipsychotic drugs. In preliminary analyses of integrated post-mortem, neuropsychological and clinical trial datasets, variation in this gene shows important regulatory effects on gene expression, interactions with a key regulator of cortical dopaminergic function, COMT, in its association with cognitive performance, and holds promise as potent predictor of therapeutic response to both antipsychotic medication and the COMT inhibitor, tolcapone. Multilocus studies of COMT, which may be particularly valuable in understanding mechanisms of cortical dysfunction in schizophrenia, (Eisenberg and Berman 2014) as well as other dopamine-related disorders (e.g., Parkinsons disease), have also progressed this year and have focused on neuroimaging outcome measurements in tolcapone trials. Along with continuing advancement on several other fronts, including multimodal pharmacological trials with modafinil, this project is well positioned for even greater scientific achievements in the coming year.